This proposal involves confirmatory as well as discovery-type proteomic analyses of protein profiles in the human cerebral spinal fluid (CSF) obtained from patients with Parkinson's disease (PD) at various stages (and _+_dementia) as compared to those of age-matched controls and patients with other neurodegenerative diseases. The utilized technologies are isotope-coded affinity tag (ICAT) labeling of samples followed by mass spectrometry (MS) analysis with or without a prior multidimensional peptide liquid chromatographic (LC) separation. In the last few years, we have employed these techniques to study novel proteins associated with a-synuclein and neurofibrillary tangles as well as age- and Alzheimer's disease-related changes in human CSF. In the proposed application, we will complement these approaches with another newly developed proteomic technique (iTRAQ) that can quantitatively compare multiple disease settings simultaneously. The goal of this study is to identify protein biomarkers unique to PD patients that can assist in clinical diagnosis of the disease and monitor its progression.*
Using a well-defined cohort of patients/controls, a great deal of data has been generated from Dr. Zhang's proteomic analyses. The major challenge in a proteomic investigation is validation of the candidate markers in a large/variedcohort of patients/controls. As the first step toward this goal, two different techniques (mass spectometry- and immunoassay-based) were used to validate a subset of markers that are unique to PD diagnosis. The preliminary studies indicated that a combination of eight markers successfully classifies PD with 95-percent sensitivity and 95-percent specificity. Hopefully, these results can be replicated by different investigators in the next few years. Currently, Dr. Zhang's group is extending its investigation to the markers unique to PD progression.
Results of this project were published in the journals Mass Spectrometry Review, Journal of Proteomic Research, Neurobiology of Disease, Proteomics - Clinical Application, American Journal of Clinical Pathology, Proteomics and the Journal of Alzheimer’s Disease.
Follow-on funding was received from the National Institutes of Health through its R01, P42, R21 and P01 grant mechanisms.